Risk factors for postoperative late deterioration in patients with spinal dural arteriovenous fistulas.

Background: Approximately 86% of patients with spinal dural arteriovenous fistulas (SDVAFs) exhibit clinical improvement after surgery. However, 12%-55.8% of these patients experience late deterioration (LD) after an initial period of improvement. The risk factors for LD remain unclear. The aim of this study was to explore the risk factors for LD in SDVAF patients. Methods: The clinical data of patients who were admitted to two tertiary hospitals between June 2014 and May 2022 were reviewed. Patients were divided into two groups: the LD group and the no LD group. The severity of neurological dysfunction (NDF) was evaluated using the Modified Aminoff and Logue Scale. Univariable and multivariable Cox regression analyses were performed. Results: A total of 105 eligible patients were enrolled, with a mean age of 57.55 ± 9.42 years. The LD group comprised 37 individuals, while the no LD group consisted of 68 individuals. According to the univariable analysis, preoperative NDF severity and treatment strategy were associated with the risk of LD. According to the multivariable analysis, patients who underwent microsurgery (MS) had a lower risk of LD than did those who underwent endovascular treatment (EVT; HR 0.197, 95% CI 0.085-0.457), and patients with severe NDF had a higher risk of LD than did those with mild NDF (HR 3.604, 95% CI 1.226-10.588), whereas the risk of LD in patients with moderate NDF was similar to that of patients with mild NDF (HR 1.352, 95% CI 0.519-3.524). Conclusion: EVT and severe preoperative NDF are independent risk factors for LD.

Conversion therapy for advanced hepatocellular carcinoma in the era of precision medicine: Current status, challenges and opportunities.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.

Case Report: A rare case of intramedullary spinal cord abscess with brain abscess caused by Klebsiella pneumoniae underwent surgical intervention.

Background: Intramedullary Spinal Cord Abscess (ISCA) is an uncommon infectious disease of the central nervous system. Since its first report in 1830, there have been very few documented cases associated with it. Here, we present a case of ISCA with cerebral abscess caused by Klebsiella pneumoniae. Case presentation: A 55-year-old male patient presented with head and neck pain, fever, and left limb weakness for 5 days. The diagnosis of ISCA with brain abscess caused by Klebsiella pneumoniae was confirmed through sputum culture, cerebrospinal fluid gene test, pus culture, and magnetic resonance imaging (MRI) as well as computerized tomography (CT) scan. The patient had a history of pulmonary tuberculosis and old tuberculous foci were observed in the lung. Initially considering tuberculosis as the cause due to unclear etiology at that time, anti-tuberculosis treatment was administered. However, due to rapid deterioration in the patient's condition and severe neurological dysfunction within a short period of time after admission, surgical intervention including incision and drainage for intramedullary abscess along with removal of brain abscess was performed. Subsequent postoperative follow-up showed improvement in both symptoms and imaging findings. Conclusion: Early diagnosis of central nervous system (CNS) abscess coupled with prompt surgical intervention and administration of appropriate antibiotics are crucial factors in preventing disease progression and reducing mortality rates.

Clinical implications and molecular features of tertiary lymphoid structures in stage I lung adenocarcinoma.

AIMS: We investigated the clinical implications and molecular features of TLS in stage I lung adenocarcinoma (LUAD). METHODS: We retrospectively reviewed the clinicopathological characteristics of 540 patients with p-stage I LUAD. Logistic regression analysis was applied to determining the relationships between clinicopathological features and the presence of TLS. TLS-associated immune infiltration pattern and signature genes were characterized using the transcriptomic profiles of 511 LUADs from The Cancer Genome Atlas (TCGA) database. RESULTS: The presence of TLS was associated with a higher pT stage, low- and middle-grade patterns, and the absence of tumor spreading through air spaces (STAS) and subsolid nodules. Multivariate Cox regression analysis identified that the presence of TLS was associated with favorable overall survival (OS) (p < 0.001) and recurrence-free survival (RFS) (p < 0.001). Subgroup analysis showed that the most favorable OS (p < 0.001) and RFS (p < 0.001) favored the TLS + PD-1- subgroup. The presence of TLS was characterized by abundance in antitumor immunocytes including activated CD8+ T and B cells as well as dentritic cells in TCGA cohort. CONCLUSION: The presence of TLS was an independent favorable factor for patients with stage I LUAD. The presence TLS was featured by special immune profiles which might aid oncologists in determining personalized adjuvant treatment.

Endothelial function and arterial stiffness indexes in subjects with carotid plaque and carotid plaque length: A subgroup analysis showing the relationship with hypertension and diabetes.

BACKGROUND: Stroke is a leading cause of death and disability globally. A large proportion of ischemic strokes are caused by carotid atherosclerotic plaques. However, the relationship between vascular health status (arterial stiffness and endothelial dysfunction) and carotid plaque remains unclear. OUR STRATEGY: Here, we recruited 991 subjects with carotid plaques and 1170 subjects without carotid plaques to measure arterial stiffness and endothelial dysfunction, using a logistic regression model and multiple linear regression models to predict the relationship between them and carotid plaques. MAIN RESULTS: The data revealed that patients with carotid plaques presented a significantly higher mean of cf-PWV and lower mean RHI values. Age, male gender, diabetes, hypertension, and smoking contributed to plaque formation. Carotid plaques and their lengths were negatively associated with RHI values and positively associated with cf-PWV values; diabetes combined with hypertension showed a cumulative effect on arteriosclerosis. CONCLUSION: RHI combined with cf-PWV could improve the efficacy of predicting the presence of carotid plaques and their lengths.

Persistent Hemodynamic Depression After Carotid Artery Stenting: A Review and Update.

According to the American Heart Association, ischemic stroke is the second leading cause of death globally and is responsible for approximately 11% of deaths. Carotid endarterectomy (CEA) is the standard treatment for moderate or severe extracranial internal carotid artery (ICA) stenoses. With the development of materials and technology in neurointervention, the Centers for Medicare and Medicaid Services (CMS) have proposed that carotid artery stenting (CAS) can serve as an alternative treatment for CEA. As CAS is widely used worldwide, comorbidities, especially persistent hemodynamic depression (PHD) and stroke, have attracted public attention. In this review, we summarized the current advances in PHD after CAS. A better understanding of CAS-related PHD may inspire the design of potential prognostic and therapeutic tools.

HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis.

Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a key enzyme in the mevalonate pathway of cholesterol synthesis. Dysregulation of HMGCS1 expression is a common occurrence in many solid tumors. It was also found to be overexpressed in newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) patients. Previous study proved that HMGCS1 could induce drug-resistance in AML cells. However, the underlying mechanism how HMGCS1 contributed to chemoresistance remains elusive. Here, we confirmed that HMGCS1 inhibitor Hymeglusin enhanced cytarabine/Adriamycin (Ara-c/ADR) chemo-sensitivity in AML cells lines. Moreover, Ara-c-resistant HL-60 cells (HL-60/Ara-c) and ADR-resistant HL-60 cells (HL-60/ADR) were more sensitive to HMGCS1 inhibition than HL-60 cells. In addition, we demonstrated that the transcription factor GATA1 was the upstream regulator of HMGCS1 and could directly bind to the HMGCS1 promoter. After treatment of Tunicamycin (Tm), the number of mitochondria was increased and the damage of endoplasmic reticulum (ER) was reduced in bone marrow cells from AML-RR patients, compared to cells from AML-CR group. HMGCS1 protected mitochondria and ER under ER stress and up-regulated unfold protein response (UPR) downstream molecules in AML cells. In summary, we proved that HMGCS1 could upregulate UPR downstream components, protect mitochondria and ER from damage in AML cells under stress, therefore conferring drug resistance. Therefore, HMGCS1 could serve as a novel target for treatment of patients with intolerant chemotherapy and AML-RR patients.

Downregulation of p53 by Insufficient CTCF in CD4+ T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease.

Recent evidence indicates that p53 plays a protective role against various systemic autoimmune diseases by suppressing pro-inflammatory cytokine production and reducing the number of pathogenic T cells. However, whether abnormal p53 expression participates in the development of acute graft-versus-host disease (aGVHD) remains unclear. In this study, we demonstrated that p53 was downregulated in CD4+ T cells from patients with aGVHD compared with the non-aGVHD group. Furthermore, we confirmed that low expression of CCCTC-binding factor (CTCF) in CD4+ T cells from aGVHD cases is an important factor affecting histone H3K9/K14 hypoacetylation in the p53 promoter and p53 downregulation. Restoring CTCF expression in CD4+ T cells from aGVHD patients increased p53 amounts and corrected the imbalance of Th17 cells/Tregs. Taken together, these results provide novel insights into p53 downregulation in CD4+ T cells from aGVHD patients.

Integration of transcriptome and cistrome analysis identifies RUNX1-target genes involved in pancreatic cancer proliferation.

The extremely high proliferation rate of tumor cells contributes to pancreatic cancer (PC) progression. Runt-related transcription factor 1(RUNX1), a key factor in hematopoiesis that was correlated with tumor progression. However, the role of RUNX1 in PC proliferation was still unclear. We found that RUNX1 was significantly upregulated in PC tissues and its expression was negatively associated with prognosis of PC patients in a multicenter analysis according to immunohistochemical (IHC). RUNX1 downregulation in PC resulted in a significantly reduced cell proliferation rate, which was consistent with in vivo subcutaneous tumor formation assay results. RNA-seq and ChIP-seq results revealed that a portion of target genes, including HAP1, GPRC5B, PTPN21, VHL and EN2, were regulated by RUNX1, a finding successfully validated by ChIP-qPCR, qRT-PCR and Western blot. Subsequently, IHC and proliferation assays showed these target genes to be dysregulated in PC, affecting tumor growth. Our data suggest that RUNX1 plays an oncogenic role in tumor proliferation and is a potential prognostic biomarker and therapeutic target for PC.

HMGB1 Recruits TET2/AID/TDG to Induce DNA Demethylation in STAT3 Promoter in CD4+ T Cells from aGVHD Patients.

STAT3 is highly expressed in aGVHD CD4+ T cells and plays a critical role in inducing or worsening aGVHD. In our preceding studies, DNA hypomethylation in STAT3 promoter was shown to cause high expression of STAT3 in aGVHD CD4+ T cells, and the process could be modulated by HMGB1, but the underlying mechanism remains unclear. TET2, AID, and TDG are indispensable in DNA demethylation; meanwhile, TET2 and AID also serve extremely important roles in immune response. So, we speculated these enzymes involved in the STAT3 promoter hypomethylation induced by HMGB1 in aGVHD CD4+ T cells. In this study, we found that the binding levels of TET2/AID/TDG to STAT3 promoter were remarkably increased in CD4+T cells from aGVHD patients and were significantly negatively correlated with the STAT3 promoter methylation level. Simultaneously, we revealed that HMGB1 could recruit TET2, AID, and TDG to form a complex in the STAT3 promoter region. Interference with the expression of TET2/AID/TDG inhibited the overexpression of STAT3 caused by HMGB1 downregulation of the STAT3 promoter DNA methylation. These data demonstrated a new molecular mechanism of how HMGB1 promoted the expression of STAT3 in CD4+ T cells from aGVHD patients.

LINC00963 Confers Oncogenic Properties in Glioma by Regulating the miR-506/BCAT1 Axis.

BACKGROUND: Glioma is a prevalent disease of the central nervous system with a high incidence and mortality rate. Many long noncoding RNAs (lncRNAs) have been determined to be critical regulators of glioma oncogenesis. However, the function and mechanism of LINC00963 in glioma have not been fully elucidated. METHODS: The expression level of RNA was determined by qRT-PCR, and the protein level was determined by Western blot analysis. A luciferase activity assay was conducted to verify the interaction between miRNA and lncRNA or the target gene. The proliferation, cell cycle distribution, invasion, and migration were evaluated by MTT, EdU, flow cytometry, wound-healing and Transwell invasion assays, respectively. In vivo tumor growth was evaluated in a xenograft nude mouse model. RESULTS: We found that LINC00963 was upregulated in glioma cells and tissues and associated with the poor prognosis of patients with glioma. Ectopic expression of LINC00963 promoted cell proliferation, cell cycle progression, migration, and invasion in vitro and tumorigenesis in vivo. Mechanistically, the results of luciferase activity and RNA pulldown assays validated that LINC00963 could act as a molecular sponge of miR-506. Reciprocal repression was found between LINC00963 and miR-506. In addition, BCAT1 was identified as a target of miR-506, and both the mRNA and protein levels of BCAT1 were reduced by miR-506. In tumor tissues, the expression of BCAT1 was negatively and positively correlated with miR-506 and LINC00963 expression, respectively. The reintroduction of BCAT1 in glioma cells abolished the tumor suppressive function of miR-506 by promoting cell viability and motility. The upregulated LINC00963 and BCAT1 were associated with the aggressive phenotypes of tumors. CONCLUSION: Our data revealed that LINC00963 confers oncogenic function in the progression of glioma and that the LINC00963/miR-506/BCAT1 axis may be a novel mechanism and therapeutic strategy for this disease.

Could tumor spread through air spaces benefit from adjuvant chemotherapy in stage I lung adenocarcinoma? A multi-institutional study.

BACKGROUND: The benefit of adjuvant chemotherapy (ACT) remains unknown for patients with stage I lung adenocarcinoma (ADC) with spread through air spaces (STAS). This study investigated the effect of adjuvant chemotherapy in stage I ADC/STAS-positive patients. METHODS: A total of 3346 patients with stage I ADC from five institutions in China were identified from 2009 to 2013, of whom 1082 were diagnosed with STAS (32.3%). By using the Kaplan-Meier method and Cox proportional hazard regression model, we explored the impact of STAS on prognosis, and determined if the use of adjuvant chemotherapy was associated with improved outcomes in patients with stage I ADC/STAS-positive. A validation cohort was also included in this study. RESULTS: Patients with stage I ADC/STAS-positive in the primary cohort had unfavorable overall survival (OS) and disease-free survival (DFS). A multivariate Cox regression model confirmed the survival disadvantages of STAS in patients with stage I ADC [OS: hazards ratio (HR) = 1.877, 95% confidence interval (CI): 1.579-2.231; p < 0.001; DFS: HR = 1.895, 95% CI: 1.614-2.225; p < 0.001]. Lobectomy was associated with better OS and DFS than sublobar resection (SR) in both stage IA and IB ADC/STAS-positive. Similar results were observed in the validation cohort. For patients with stage IB ADC/STAS-positive, ACT was revealed as an independent factor for favorable survival (OS: HR = 0.604, 95% CI: 0.397-0.919; p = 0.018; DFS: HR = 0.565, 95% CI: 0.372-0.858; p = 0.007). However, among patients with stage IA ADC/STAS-positive, ACT was associated with improved outcomes only for those undergoing SR (OS: HR = 0.787, 95% CI: 0.359-0.949; p = 0.034; DFS: HR = 0.703, 95% CI: 0.330-0.904; p = 0.029). CONCLUSION: The presence of STAS was correlated with poor prognosis in patients with stage I ADC. Our study suggested that ACT might be considered for patients with stage IB ADC/STAS-positive and those with stage IA ADC/STAS-positive who underwent SR.

Long-term survival of an elderly patient with advanced gastric cancer after combination therapy: a case report and literature review.

BACKGROUND: Gastric cancer ranks the fifth most common cancer, and the third leading cause of cancer-related deaths worldwide. Gastric cancer with liver metastasis (GCLM) has devastating prognosis, however, optimal treatment of GCLM, especially in elderly patients, has yet to be clarified. CASE PRESENTATION: A 75-year-old man was diagnosed with advanced gastric cancer (GC), presenting with acute gastrointestinal bleeding and synchronous metastatic lesion in liver. Based on multidisciplinary team (MDT)'s decision, this patient underwent distal palliative gastrectomy with R1 margin. Histopathological diagnosis was stage IV gastric adenocarcinoma (pT3N2M1), HER2 negative. The patient was treated with chemotherapy and argon-helium cryoablation of liver and lung metastases.HER-2 gene amplification was identified in peripheral blood at later stage of therapy. The patient had been followed-up for 39 months, in sharp contrast to a median survival time of 13.8 months for majority of advanced GC. CONCLUSIONS: Palliative distal gastrectomy in combination with chemotherapy and cryoablation significantly prolongs overall survival of an elderly patient with GCLM.

Correction: Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma.

[This corrects the article DOI: 10.18632/oncotarget.8368.].

Improved dialysis removal of protein-bound uremic toxins by salvianolic acids.

BACKGROUND: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) are two key protein-bound uremic toxins that accumulate in patients with end-stage renal disease. IS and pCS cannot be efficiently removed by conventional hemodialysis because they are highly bound to proteins. One promising means to optimize the removal of protein-bound uremic toxins involves using binding competitors to liberate uremic toxins from protein-binding partners. PURPOSE: In this study, we try to identify potential binding competitors that can enhance the dialysis removal of IS and pCS in natural compounds of phytomedicine. METHODS: We employed microdialysis to evaluate whether Danhong injection (DHI) and its salvianolic acids can increase the free fractions of IS and pCS and thus improve their dialysis efficiency in vitro. Furthermore, we confirmed the positive effects of DHI and salvianolic acids in vivo on chronic kidney disease model rats in which IS and pCS had heavily accumulated. RESULTS: DHI significantly increased the dialysis efficiency of IS and pCS by 99.13% and 142.00% in vitro (10-fold dilution), respectively, and by 135.61% and 272.13% in vivo (4.16 ml/kg). Salvianolic acids including lithospermic acid (LA), salvianolic acid A (SaA), tanshinol (DSS), caffeic acid (CA), salvianolic acid B (SaB), protocatechuic aldehyde (PA) and rosmarinic acid (RA) significantly enhanced the dialysis removal of IS and pCS in a concentration-dependent manner. LA, the best competitor of the tested salvianolic acids, increased dialysis efficiency levels of IS and pCS by 197.23% and 198.31% in vitro (400 µM), respectively, and by 119.55% and 127.56% in vivo (24.69 mg/kg). CONCLUSION: The removal of protein-bound uremic toxins IS and pCS using DHI or salvianolic acids as protein-bound competitors is superior to previously reported strategies and drugs and may contribute to clinical hemodialysis therapeutic practice.

Microarray expression profile analysis of circular RNAs in pancreatic cancer.

Pancreatic cancer remains one of the most malignant tumors with a poor prognosis. Despite advances in diagnosis and treatment, no reliable biomarkers are available for clinical practice. Circular RNAs (circRNAs) are a novel class of endogenous non­coding RNA, which are abundant, stable and conserved, and serve crucial roles in disease, particularly in cancer. The purpose of the present study was to investigate the expression profile of circRNAs in 20 pancreatic cancer tissues and corresponding paracancerous tissues using arraystar human circRNA array analysis, high­throughput circRNA microarray, bioinformatic analysis and reverse transcription­quantitative polymerase chain reaction. It was revealed that the circRNAs expression profile was significantly different between pancreatic cancer tissue and paracancerous tissue, which indicates a potential role in pancreatic cancer. It was predicted that circRNAs may act as a micro RNA sponge to modulate gene expression in pancreatic cancer. Additionally, microarray expression analysis data was submitted to the Gene Expression Omnibus under accession no. GSE79634. The present study revealed that circRNAs expression was visibly diverse in pancreatic cancer compared with paracancerous tissue and provides more reliable biomarkers and new insights into the mechanisms of pancreatic cancer.